Metastatic migration of the murine L1210 leukemia and an L-phenylalanine mustard resistant variant (L1210/L-PAM) from the peritoneal cavity and infiltration into the liver results in a 2-fold increase in the glutathione (GSH) content of both tumor cells. These increases in the cellular content of GSH are accompanied by a 2-fold increase in the resistance of these tumor cells to L-phenylalanine mustard. Cell surface labeling studies indicate that cells isolated from the liver have a 5-fold greater content of surface sulfhydryl groups as compared to their ascitic counterparts. The former can be sensitized to L-phenylalanine mustard by blocking these sulfhydryl groups by continuous exposure of cells to 6-6' dithiodinicotinic acid. Studies utilizing co-cultures of murine hepatocytes and murine leukemia cells in serum-free medium indicate an absolute requirement for the hepatocyte in the promotion of tumor cell growth. These results demonstrate a determinant role of the hepatic microenvironment in tumor cell growth, maintenance of tumor cell GSH, cell surface sulfhydryl groups and the sensitivity of these tumor cells to L-phenylalanine mustard.